10009fnl 2-20-13

7/21/2019 10009fnl 2-20-13

1/34

Guidance for Industry

Labeling for Human Prescription

Drug and Biological Products

Implementing the PLR Content and

Format Requirements

U.S. Department of Health and Human Services

Food and Drug AdministrationCenter for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

February 2013

Labeling

7/21/2019 10009fnl 2-20-13

2/34

Guidance for Industry

Labeling for Human PrescriptionDrug and Biological Products

Implementing the PLR Content and

Format Requirements

Additional copies are available from:

Office of Communications

Division of Drug Information, WO51, Room 2201

10903 New Hampshire Ave.

Silver Spring, MD 20993

Phone: 301-796-3400; Fax: 301-847-8714

[email protected]://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

or

Office of Communication, Outreach and

Development, HFM-40Center for Biologics Evaluation and Research

Food and Drug Administration

1401 Rockville Pike, Rockville, MD 20852-1448

[email protected]://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

(Tel) 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

February 2013

Labeling
mailto:[email protected]://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmmailto:[email protected]://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htmmailto:[email protected]://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmmailto:[email protected]://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

7/21/2019 10009fnl 2-20-13

3/34

Contains Nonbinding Recommendations

TABLE OF CONTENTS

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND ............................................................................................................... 2

III. CONSIDERATIONS FOR REVISING LABELING.................................................... 2

A. Developing New Sections............................................................................................................... 3

B. Data Analyses or New Studies ...................................................................................................... 3

C. Updating Information in Labeling ............................................................................................... 4

IV. DISTRIBUTING INFORMATION AMONG SECTIONS .......................................... 4

A. Organizing Information to Avoid Redundancy .......................................................................... 4

B. Using Cross-References ................................................................................................................. 5

C. Example of the Distribution of Information Among Labeling Sections ................................... 5

V. HIGHLIGHTS .................................................................................................................. 6

A. General Principles.......................................................................................................................... 6

B. Information in Highlights.............................................................................................................. 7

1. Highlights Title and Limitation Statement ( 201.56(d)(1) and 201.57(a)(1)) ....................... 7

2. Product Title: Drug Names, Dosage Form, Route of Administration, and Controlled

Substance Symbol ( 201.57(a)(2)) ........................................................................................... 7

3. Initial U.S. Approval ( 201.57(a)(3))....................................................................................... 7

4. Boxed Warning ( 201.57(a)(4)) ............................................................................................... 7

5. Recent Major Changes ( 201.57(a)(5)) ................................................................................... 8

6.

Indications and Usage ( 201.57(a)(6)).................................................................................. 11

7.

Dosage and Administration ( 201.57(a)(7)) .......................................................................... 11

8. Dosage Forms and Strengths ( 201.57(a)(8)) ....................................................................... 12

9. Contraindications ( 201.57(a)(9))......................................................................................... 12

10. Warnings and Precautions ( 201.57(a)(10)) ......................................................................... 13

11. Adverse Reactions ( 201.57(a)(11)) ...................................................................................... 13

12. Drug Interactions ( 201.57(a)(12)) ....................................................................................... 15

13. Use in Specific Populations ( 201.57(a)(13))........................................................................ 15

14. Patient Counseling Information Statement ( 201.57(a)(14))................................................. 16

15. Revision Date ( 201.57(a)(15)) ............................................................................................. 16

VI. FORMATTING............................................................................................................... 17

A. Subsection Headings .................................................................................................................... 17

B. Omitted Sections ( 201.56(d)(4)) ............................................................................................... 18

C. Cross-References.......................................................................................................................... 18

D. Type Size and Font Type............................................................................................................. 18

E. Use of Abbreviations.................................................................................................................... 19

VII. PROCEDURAL INFORMATION................................................................................ 19

A. Applications Covered by the Final Rule .................................................................................... 19

i

7/21/2019 10009fnl 2-20-13

4/34


1. New NDAs, BLAs, and Efficacy Supplements ......................................................................... 19

2. Approved Applications ............................................................................................................ 20

3. Submitting Draft Labeling to FDA for Review........................................................................ 20

B. Changes to the Regulations for Applications Not Covered by the Final Rule ....................... 21

C. Appending FDA-Approved Patient Labeling............................................................................ 21

D. Submitting Electronic Versions of Labeling.............................................................................. 22

E. Waivers and CBE Supplements.................................................................................................. 22

F. Class Labeling .............................................................................................................................. 23

1. Mandated Statements .............................................................................................................. 23

2. Class Labeling Statements That Are Not Mandated by Regulation ........................................ 23

G. Abbreviated New Drug Application (ANDA) Products ........................................................... 24

H. 505(b)(2) NDA Products .............................................................................................................. 24

I. Manufacturer Information ......................................................................................................... 24

VIII. ADDITIONAL LABELING GUIDANCES ................................................................. 25

APPENDIX A IMPLEMENTATION PLAN...................................................................... 26

APPENDIX B PRESCRIPTION DRUG LABELING SECTIONS.................................. 27

APPENDIX C REORGANIZING LABELING SECTIONS ............................................ 28

APPENDIX D TYPE SIZE REQUIREMENTS FOR LABELING AND FDA-

APPROVED PATIENT LABELING INCLUDED WITH LABELING............................... 29

APPENDIX E HIGHLIGHTS AND CONTENTS FORMAT SAMPLE.......................... 30

ii

7/21/2019 10009fnl 2-20-13

5/34


Guidance for Industry1

Labeling for Human Prescription Drug and Biological Products2

Implementing the PLR Content and Format Requirements3

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It

does not create or confer any rights for or on any person and does not operate to bind FDA or the public.

You can use an alternative approach if it satisfies the requirements of the applicable statutes and

regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for

implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate

number listed on the title page of this guidance.

I. INTRODUCTION

This guidance is intended to assist applicants in complying with the content and format

requirements of labeling for human prescription drug and biological products under 21 CFR201.56(d) and 201.57. FDA is issuing this guidance to provide recommendations for applicants

developing labeling for new prescription drugs and revising labeling for already approved

prescription drugs. This guidance also provides recommendations on developingHighlights of

Prescribing Information(Highlights), formatting labeling, and procedural information.

FDA's guidance documents, including this guidance, do not establish legally enforceableresponsibilities. Instead, guidances describe the Agency's current thinking on a topic and should

be viewed only as recommendations, unless specific regulatory or statutory requirements are

cited. The use of the word shouldin Agency guidances means that something is suggested or

recommended, but not required.

1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research

(CDER) and Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.2This guidance applies to drugs, including biological drug products. For the purposes of this guidance, drugor drug

product will be used to refer to human prescription drug and human prescription biological products that are

regulated as drugs.3See the final rule Requirements on Content and Format of Labeling for Human Prescription Drug and Biological

Products, 71 FR 3922, January 24, 2006. This rule is commonly referred to as the Physician Labeling Rule(PLR)

because it addresses prescription drug labeling that is used by prescribers and other health care professionals.

1

7/21/2019 10009fnl 2-20-13

6/34


II. BACKGROUND

On January 24, 2006, FDA published a final rule that amended the requirements for the content

and format of labeling for human prescription drug and biological products. The rule is

commonly referred to as the Physician Labeling Rule(PLR) because it addresses prescriptiondrug labeling that is used by prescribers and other health care practitioners. The rule was

designed to make information in prescription drug labeling easier for health care practitioners toaccess, read, and use to facilitate practitioners use of labeling to make prescribing decisions.

Labeling includes three sections: Highlights of Prescribing Information (Highlights), a Table of

Contents (Contents), and the Full Prescribing Information (FPI). Highlights contains selectedinformation from the FPI that health care practitioners most commonly reference and consider

most important. Contents lists the sections and subsections of the FPI. FPI contains the detailed

prescribing information necessary for safe and effective use of the drug. The final rule alsoreordered and reorganized the FPI, made minor changes to the content of the FPI, and set

minimum graphic requirements for the format of the labeling.

Not all drugs are subject to the labeling requirements under 201.56(d) and 201.57. The finalrule is being implemented on a staged implementation schedule that, based on approval date or

application status, requires new and recently approved prescription drugs to comply with these

labeling requirements by a particular date (see 201.56(b) and Appendix A). Prescription drugsthat are not subject to 201.56(d) and 201.57 are subject to the labeling requirements under

201.56(e) and 201.80. The final rule also made minor changes to these regulations.

For the purpose of this guidance, the term PLR formatrefers to labeling that meets the content

and format requirements at 201.56(d) and 201.57. The term old formatrefers to labeling that

meets the requirements at 201.56(e) and 201.80. See Appendix B for a listing of prescription

drug labeling sections in the old and PLR formats.

In general, the most challenging aspects of this regulation are developing Highlights and

distributing information among sections that have been substantially affected by the rule,particularly when the information originates from the labeling in the old format. Therefore, the

guidance focuses primarily on these issues. Additional guidance documents that address content

and format for specific FPI sections are available and should be consulted when developinglabeling (see section VIII of this document).

III. CONSIDERATIONS FOR REVISING LABELING

The FPI in the PLR format contains substantially the same information as labeling in the old

format, typically with reordering and reorganization of the information. For example, new

labeling sections (e.g., DRUG INTERACTIONS, USE IN SPECIFIC POPULATIONS,PATIENT COUNSELING INFORMATION) contain information formerly included in the

PRECAUTIONS section. Certain sections (e.g., CLINICAL STUDIES, NONCLINICALTOXICOLOGY) that were previously optional are now required if applicable ( 201.56(d)).

Therefore, although labeling in the old format for approved products does not contain the new

section headings, most of the content already is included in the labeling under different headings

2

7/21/2019 10009fnl 2-20-13

7/34


or subheadings. For example, information from the old WARNINGS section and oldPRECAUTIONS section is consolidated into a single new section (WARNINGS AND

PRECAUTIONS) and information in certain old PRECAUTIONS subsections (e.g.,Information

for Patients,Drug Interactions, Pregnancy,Labor and Delivery,Nursing Mothers, PediatricUse, Geriatric Use) is relocated to new labeling sections (e.g., PATIENT COUNSELING

INFORMATION, DRUG INTERACTIONS, USE IN SPECIFIC POPULATIONS).

Making the transition to the PLR format provides an ideal opportunity to review the labelingcontent for general quality (e.g. format, organization, and readability) and to make it a better

communication tool. FDA recommends following these general principles when converting

labeling in the old format to the PLR format.

A. Developing New Sections

FDA expects that most sections or subsections from labeling in the old format can be moved,

with little or no modification, to corresponding sections in the PLR format (see Appendix C).

However, the labeling in the old format may not include the information specified by the newregulations, or the content of a section may not adequately reflect scientific information neededfor safe and effective use of the drug. In this case, the labeling must be updated ( 201.56(a)).

If the labeling in the old format lacks an entire section that is required in the PLR format, thesection must be developed unless it is clearly inapplicable ( 201.56(d)). For example, if the

labeling in the old format does not contain anInformation for Patientssubsection in the

PRECAUTIONS section, the applicant must develop a PATIENT COUNSELINGINFORMATION section because, with only limited exceptions, there will be important

information about a drug for the prescriber to convey to the patient or caregiver. In another

example, it may not be necessary to develop a CLINICAL STUDIES section for certain older

products (e.g., when data are not readily available).

B. Data Analyses or New Studies

FDA recognizes that revising labeling to comply with the PLR regulations is an excellent

opportunity to update labeling content to ensure that it accurately reflects current knowledge.

FDA expects that, in most cases, the revisions will involve limited rewriting aimed at clarifyingtext, eliminating redundancies, and updating outdated terminology. Generally, no new data

analyses of the information in the old format are required if the labeling is truthful and accurate.

However, if new information is available that causes the labeling to be inaccurate, the labeling

must be updated to incorporate the new information ( 201.56(a)(2)). In some cases, a re-analysis of the data may be necessary.

Furthermore, if essential information is missing from the labeling (e.g., new information about aclass drug interaction), this information must be included ( 201.56(a)(2)). In this case, the

review division would determine the need for a new study, a decision that would be madeindependent of the labeling conversion process.

3

7/21/2019 10009fnl 2-20-13

8/34


C. Updating Information in Labeling

By regulation, all express or implied claims in labeling must be supported by substantial

evidence.4 If unsubstantiated claims currently exist in labeling, the applicant must revise the

labeling to remove such claims ( 201.56(a)(3)). Although the content of labeling in the old

format will not substantially change when converted to PLR format, the applicant shouldsystematically evaluate information in labeling to identify unsubstantiated claims or outdated

information and revise it accordingly.

Revisions to the content requirements in certain sections may result in the need to review and

revise those sections. For example, consider the ADVERSE REACTIONS section. For thepurposes of prescription drug labeling, the definition of adverse reaction in 201.57(c)(7) was

revised to clarify that it does not include all adverse events observed during use of a drug, only

those adverse events for which there is some basis to believe there is a causal relationshipbetween the drug and the occurrence of the adverse event. When updating labeling, the applicant

should review the ADVERSE REACTIONS section to ensure all events appropriately fall under

that section and delete those events unlikely to have been caused by the drug (i.e., usually alengthy listing commonly referred to as the laundry list). Because such a list is not essential tothe safe and effective use of the drug, it should simply be omitted.

The OVERDOSAGE section is another example of a labeling section that is typically notrevisited after initial approval. However, postmarket experience with overdose may inform new

management recommendations for the drug product and the labeling content should be updated

to reflect current knowledge.

IV. DISTRIBUTING INFORMATION AMONG SECTIONS

When creating labeling in PLR format or converting labeling in the old format to the PLRformat, applicants face many decisions about how to distribute information among labeling

sections. Often sections or subsections can be moved with little or no modification (see

Appendix C). In some cases, it will be more appropriate to move certain information from alabeling section in the old format to a different labeling section in the PLR format or to

consolidate similar issues in one place. In other cases, it will be appropriate to divide portions of

information in a single labeling section among two or more sections. The following generalprinciples and examples are offered to help applicants make decisions about how to organize

information. These considerations apply whether revising labeling from the old format or

creating new labeling.

A. Organizing Information to Avoid Redundancy

Clinical information pertinent to prescribing decisions should be identified, prioritized, andlocated in the labeling section that most appropriately communicates the type of information.

Detailed information about a particular topic should be consolidated in a single labeling section.

4See 201.56(a)(3). See also 201.57(c)(2)(iii), (c)(2)(iv), (c)(2)(v), (c)(7)(iii), and (c)(15)(i), and

201.80(c)(2)(i), (c)(2)(ii), (g)(4), and (m)(1)(i).

4

7/21/2019 10009fnl 2-20-13

9/34


Other sections of labeling may more briefly describe or refer to the topic, but not repeat the samecontent or level of detail. For example, information about a drug interaction that rises to the

level of a warning will be described in the WARNINGS AND PRECAUTIONS section, with

supporting detail in the DRUG INTERACTIONS section and other sections as appropriate (e.g.,

DOSAGE AND ADMINISTRATION section if a dosage modification is necessary).

In some instances, information discussed in multiple sections of labeling in the old format can be

consolidated in the PLR format. For example, if the old WARNINGS and old PRECAUTIONSsections each contained information about a similar topic, this information should now be

consolidated under one subsection in the new WARNINGS AND PRECAUTIONS section.

When consolidating information, subsections can be created and should be put in an order thatreflects the contents importance and relative public health significance.

In addition, information may need to be reordered to enhance labeling organization, presentation,and ease of use (e.g., information in the DOSAGE AND ADMINISTRATION section should be

reordered to correspond to the order of the presentation of the indications in the INDICATIONS

AND USAGE section).

B. Using Cross-References

When a topic is discussed in more than one section of labeling, the section containing the mostimportant information relevant to prescribing should typically include a succinct description and

should cross-reference sections that contain additional detail. If the detailed information is

divided appropriately into more than one section, those sections should cross-reference eachother. Cross-references from the more detailed discussion to the less detailed discussion should

generally not be necessary (e.g., a succinct BOXED WARNING should reference the fuller

discussion of the risk in WARNINGS AND PRECAUTIONS, but the WARNINGS AND

PRECAUTIONS section should not refer back to the BOXED WARNING). In some cases,cross-references are required (e.g., 201.57(c)(1), (c)(6)(iv), and (c)(15)(ii)).

C. Example of the Distribution of Information Among Labeling Sections

Several basic principles are illustrated in the following example. Although drug interaction

information has been selected for this example, these principles also apply to other labelingsections.

Drug interaction information should typically appear in the DRUG INTERACTIONS and

CLINICAL PHARMACOLOGY sections. If there is a subset of information that is essential

for prescribing decisions, that subset of information can be distributed among severalsections, including the BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND

PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections (e.g., 201.57(c)(3)(i)(H) and (c)(8)).

When drug interaction information rises to the level of a contraindication, or a warning or

precaution that necessitates a dosage adjustment, this information should be presented

5

7/21/2019 10009fnl 2-20-13

10/34


succinctly in the applicable section(s), with details in the DRUG INTERACTIONS section (201.57(c)(8)).

The DRUG INTERACTIONS section contains clinically relevant information, such as the

need to modify a dose or regimen. FDA recommends using a descriptive header of summary

concepts preceding a discussion of specific information (e.g., CYP3A Inhibitors).

More detail about drug interaction studies, including those demonstrating no drug interaction(i.e., pertinent negatives), and any clinically relevant, nonclinical data should be included in

the CLINICAL PHARMACOLOGY section.

V. HIGHLIGHTS

The purpose of Highlights is to provide immediate access to the information to whichpractitioners most commonly refer and regard as most important. Highlights also helps guide the

practitioner to the section in the FPI where details can be obtained about a specific topic. The

following information is intended to help applicants develop Highlights.

A. General Principles

Highlights should be a concise, informative summary of crucial prescribing information, not a

verbatim repetition of selected material from the FPI, or a repetition of the Contents. Rarely, it

may be appropriate to repeat content verbatim from the FPI (e.g., a succinct boxed warning

statement or short indication statement), but in most cases, the information should besummarized and presented in an easily accessible format (e.g., bulleted, tabular).

The information in Highlights is derived from the FPI. Selecting the material to include in

Highlights requires judgment about the importance of the data in relation to the clinical setting inwhich the drug is used.

When information about a risk appears in more than one section of the FPI, the information

should typically be presented once in Highlights under the most appropriate heading. Forexample, if a drug interaction is described under Warnings and Precautions in Highlights, it

should not be repeated under Drug Interactions in Highlights.

Summarized information should be presented in clear language that is succinct and imparts the

most relevant and complete information. For example, under Warnings and Precautions, the

statement in Highlights should, as appropriate, identify the risk, its consequences, and the actions

to take to prevent or mitigate it. Directive language is preferable, because it conveys explicitinformation most concisely (e.g., Discontinue, as opposed to You should discontinue). Each

summarized statement should be located under the appropriate Highlights heading and must

cross-reference the section(s) or subsection(s) of the FPI that contains more detailed information( 201.56(d)(3)). If new information is to be added to Highlights, the existing information

should be evaluated and combined so that the new information can be added while maintaining

the required half page length.

6

7/21/2019 10009fnl 2-20-13

11/34


B. Information in Highlights

The following recommendations focus on the content that should be included in Highlights.

Because of the importance of the information in Highlights and the space limitations, there are

specific formatting requirements applicable to Highlights that were designed to enhance

readability and accessibility of labeling information (see 201.57(d) and section VI of thisdocument).

1. Highlights Title and Limitation Statement ( 201.56(d)(1) and 201.57(a)(1))

The title HIGHLIGHTS OF PRESCRIBING INFORMATIONmust be presented at

the beginning of Highlights ( 201.56(d)(1)). On the first line under the title, the

following Highlights Limitation Statement must be presented verbatim in bold: These

highlights do not include all the information needed to use (insert name of drug

product) safely and effectively. See full prescribing information for (insert name of

drug product)( 201.57(a)(1) and 201.57(d)(5)). We recommend that the name of the

drug product be presented in upper case letters to improve its prominence.

2. Product Title: Drug Names, Dosage Form, Route of Administration, and

Controlled Substance Symbol ( 201.57(a)(2))

The bolded product title consisting of the proprietary name and the established name of

the drug, if any, or, for biological products, the proper name must be presented,5followed

by the dosage form, and route of administration ( 201.57(a)(2) and 201.57(d)(5)). For

controlled substances, the symbol for the assigned controlled substance schedule must be

included at the end of the line ( 201.57(a)(2) and 201.57(d)(5)).

3. Initial U.S. Approval ( 201.57(a)(3))

On the line immediately beneath the product title line, the verbatim statement: Initial

U.S. Approvalmust be presented, followed by the bolded four-digit year in which FDA

initially approved a new molecular entity, new biological product, or new combination of

active ingredients ( 201.57(a)(3) and 201.57(d)(5)), regardless of dosage form orindication (i.e., multiple dates should not be listed for different dosage forms or

indications).

4. Boxed Warning ( 201.57(a)(4))

The Boxed Warning in Highlights must contain a concise summary of all of the risks

described in the BOXED WARNING in the FPI ( 201.57(a)(4)) and is limited in lengthto 20 lines, not including the title and required reference to the complete boxed warning

in the FPI. The title of the Boxed Warning must appear after the word WARNING:andmust identify the subject(s) of the warning contained in the box (e.g., WARNING:ACUTE HEPATIC FAILURE and INFUSION REACTIONS) ( 201.57(a)(4)). The

5For drugs, see section 502(e)(3) of the Federal Food, Drug, and Cosmetic Act (FD&C Act). For biological

products, see 21 CFR 600.3.

7

7/21/2019 10009fnl 2-20-13

12/34


italicized verbatim statement: See full prescribing information for complete boxed

warningmust be placed immediately following the title of the boxed warning (

201.57(a)(4)). FDA recommends that both the title and the verbatim statement be

centered within the box, and all text within the box must be in bold ( 201.57(d)(5)).

The information summarized under the Boxed Warning heading in Highlights shouldemphasize the information contained in the BOXED WARNING section of the FPI and

direct attention to the complete box and to the sections in the FPI that contain moredetailed information. Because the Boxed Warning in Highlights must be a concise

summary of the information from the complete BOXED WARNING in the FPI, no

information should be presented in the Highlights box that does not appear in the FPI box( 201.57(a)(4)). There should be only one box in the FPI and one summarized box in

Highlights, even when multiple topics are presented.

FDA recommends that the information under the Boxed Warning heading in Highlights

be summarized in a bulleted format. Formatting should facilitate the clear presentation of

complex information and risks. For example, each bullet should communicate a discretewarning, clinical indication, or contraindication. In rare instances, the BOXEDWARNING in the FPI may be sufficiently concise to warrant repeating the text verbatim

under the Boxed Warning heading in Highlights.

5. Recent Major Changes ( 201.57(a)(5))

When substantive labeling changes have been made to any of the following sections ofthe FPI within the preceding 12 months, the heading(s) of the changed section(s) must be

listed in Highlights under the heading Recent Major Changes ( 201.57(a)(5)):

Boxed Warning Indications and Usage

Dosage and Administration

Contraindications

Warnings and Precautions

Changes that must not be listed in Recent Major Changes include:

Changes to sections other than the five listed above

Changes that are not substantive (i.e., minor revisions such as correcting

typographical errors or grammatical changes)

Changes resulting from converting to the PLR format alone

a. What must be included

Each listing must include the section heading, the subsection heading (if appropriate),

identifying number of the corresponding changed section or subsection, and the date on

which the change was incorporated in the labeling (i.e., date the supplement wasapproved) in month/year format (e.g., 6/2010 or Jun 2010) ( 201.57(a)(5)).

8

7/21/2019 10009fnl 2-20-13

13/34


b. Multiple labeling changes

If there are changes to more than one section of the labeling, the listings in Recent Major

Changes must be presented in the order in which they appear in the FPI ( 201.57(a)(5)),

and not ordered by dates of the changes.

If there is more than one change in the same labeling section or subsection in thepreceding 12 months, only the newest date should be listed. For example, if a new

indication (hypertension) was added to the labeling in March 2011, and a limitation to the

hypertension indication was added in June 2011, the change under the Recent MajorChanges heading should be listed as:

Indications and Usage, Hypertension (1.2) 6/2011

Only when space in Highlights permits, if there are changes within a section to more than

one subsection during the 1-year period listed, each section heading, subsection heading,identifying number, and date should be listed separately. For example:


Indications and Usage, Heart Failure (1.3) 9/2011

If there are changes within a section to more than one subsection during the 1-year period

listed and listing subsection headings separately as above would cause Highlights to begreater than one-half page in length, only the main section heading should be listed, with

the date of the most recent change. For example:

Indications and Usage (1) 9/2011

Experience has shown that listing each changed subsection on a separate line when

multiple changes have occurred often leads to Highlights that is longer than one-halfpage. Despite not listing each subsection individually in Recent Major Changes, the

labeling will still enable the reader to readily identify the changes through the use of the

vertical lines adjacent to the new or modified text in the FPI required by 201.57(d)(9).

c. Listing related information from different FPI sections

When a drug product is approved for a new indication, new information is often added toother sections of labeling (e.g., DOSAGE AND ADMINISTRATION, ADVERSE

REACTIONS, CLINICAL STUDIES). If there are changes to any of the five applicable

sections, each changed section must be listed under the Recent Major Changes heading (201.57(a)(5)). For example:


Dosage and Administration, Hypertension (2.2) 6/2011

9

7/21/2019 10009fnl 2-20-13

14/34


d. Marking text in the FPI with a vertical line

The corresponding new or modified text in the FPI sections listed under Recent Major

Changes must be marked with a vertical line on the left edge ( 201.57(d)(9)) to alert the

reader to the new information. If new text in the FPI is very brief (e.g., 1-2 lines long), it

may be appropriate to use spacing to extend the vertical line by 1-2 additional lines (e.g.,mark the blank line before and after the new text) to make it more visible. Similarly, if a

new sentence has been added to an existing paragraph, it may be appropriate to mark theentire paragraph.

e. Deletions from labeling

Although it is unusual for information to be completely deleted from labeling (e.g.,

removing a warning as opposed to revising it or moving the discussion to a differentsection), if such a situation occurs, the applicant should propose labeling that identifies

the change in both Recent Major Changes in Highlights and in the FPI. In some cases, the

deletion may best be addressed by adding new text elsewhere in the FPI; in other cases,the Agency will determine how best to identify the change.

f. Initial submission of revised labeling in the PLR format

Applicants should list under the Recent Major Changes heading any substantive labeling

changes to the relevant sections that were approved within 1 year of submission of the

draft labeling for review in the PLR format.

g. Removing a listing from Recent Major Changes

A changed section must be listed under Recent Major Changes for at least 1 year after thedate the labeling change was approved and can continue to be listed until the labeling is

reprinted for the first time after the 1-year period expires ( 201.57(a)(5)). When the 1-

year time period expires, the applicant can choose (1) to reprint labeling immediately toremove the listing or (2) to wait until the next reprinting to remove the listing. Whenever

a supplemental application is submitted, the applicant should review the labeling changes

listed under the Recent Major Changes heading and delete any listings that are over 1year old. FDA recommends that applicants notify the Agency in an Annual Report about

removal of a listing from Recent Major Changes and the corresponding vertical line in

the FPI (see 21 CFR 314.70(b)(2)(v)(C)(1) and 601.12(f)(3)(i)(D)(1)).

h. Listing Recent Major Changes for Changes Being Effected (CBE)

Supplements6

For labeling changes made through a CBE supplement that meet the criteria for listing in

Recent Major Changes, the change must be listed under Recent Major Changes for atleast 1 year after the date the labeling change is made and can continue to be listed until

the labeling is reprinted for the first time after the 1-year period expires ( 201.57(a)(5)).

6See 314.70(c)(6) and 601.12(f)(2).

10

7/21/2019 10009fnl 2-20-13

15/34


If a further change is made to the labeling when the Agency approves the CBEsupplement, the date of approval becomes the new date from which the 1-year period is

calculated. As above, when the 1-year time period expires, the applicant can choose to

(1) reprint labeling immediately to remove the listing or (2) wait until the next reprinting

to remove the listing.

6. Indications and Usage ( 201.57(a)(6))

Information under the Indications and Usage heading in Highlights must include a

concise statement of each of the drugs indications from the FPI, briefly noting any major

limitations of use ( 201.57(a)(6)). FDA recommends that the information be presentedin a bulleted format if multiple indications exist. In some circumstances, it may be

appropriate to present the indications with the same wording as in the FPI (e.g., when a

product has one indication and the statement in the FPI is sufficiently concise).

If the FPI includes any limitations of use, the presentation in Highlights needs to be clear

as to whether the limitation applies to all indications or only certain indications. For aproduct with limitations of use that are applicable to all of the products indications, it isappropriate to list those limitations or concerns together, under an appropriately titled

subheading (e.g., Limitations of Use). If the drug is approved under 314.510 or

601.41 (i.e., an accelerated approval), a statement regarding the basis for approval shouldbe included.

If the drug is a member of an established pharmacologic class, the information underIndications and Usage must include the statement (Drug) is a (name of class) indicated

for (indication(s)) ( 201.57(a)(6)). If the drug is not a member of an established

pharmacologic class, the applicant should propose one.7 The FDA will then determine

whether to assign a new or existing pharmacologic class to the drug or to omit apharmacologic class entirely.

7. Dosage and Administration ( 201.57(a)(7))

Information under the Dosage and Administration heading must contain a concise

summary of the recommended dosage regimen (e.g., starting dose, dose range, titrationregimens, route of administration), critical differences among population subsets,

monitoring recommendations, if any, and other clinically significant clinical

pharmacology information that affects dosing recommendations (e.g., dosing adjustments

recommended for concomitant therapy, specific populations with coexisting conditions,clinically relevant food effects) ( 201.57(a)(7)). FDA recommends a tabular format to

7See FDA Guidance for Industry:Labeling for Human Prescription Drug and Biological Products Determining

Established Pharmacologic Class for Use in the Highlights of Prescribing Informationand the web page on

pharmacologic class at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm162549.htm.

We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA

Drugs guidance web site at

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

11
http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm162549.htmhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmhttp://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm162549.htmhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

7/21/2019 10009fnl 2-20-13

16/34


enhance accessibility of information as appropriate (e.g., when there are complex dosageregimens or different dosing regimens for different indications).

In general, every attempt should be made to include the critical dosing and administration

information in Highlights. However, there may be instances when a cross-reference to

the FPI for detailed information may be necessary for a product with complex dosing andadministration information. In such instances, a statement should be included under the

Dosage and Administration heading in Highlights to alert the prescriber that additionalimportant information is in the FPI.

8. Dosage Forms and Strengths ( 201.57(a)(8))

Information under the Dosage Forms and Strengths heading must include all available

dosage forms and strengths (see 201.57(a)(8)) to assist the prescriber in productselection. If a solid oral dosage form is functionally scored, such information must be

included8( 201.57(a)(8)). If a drug product has numerous dosage forms, bulleted

subheadings (e.g., capsules, suspension, injection) or tabular presentations arerecommended. For some products, including limited information on packaging canfacilitate prescribing (e.g., noting that a 0.5% topical cream is available in both 15 g and

30 g tubes). Because of space constraints in Highlights, multiple strengths for a dosage

form should be listed on one line (e.g., Tablets: 25 mg, 50 mg, 100 mg, and 200 mg).Descriptors of the product appearance (e.g., tablet color, shape, embossing) that appear in

DOSAGE FORMS AND STRENGTHS in the FPI should not appear in Highlights.

9. Contraindications ( 201.57(a)(9))

Information under the Contraindications heading must include a list of all the

contraindicated situations described in the FPI or the word None if no contraindicatedsituations have been identified ( 201.57(a)(9)). FDA recommends that each

contraindication be identified in a bulleted list.

As in the FPI, theoreticalcontraindications should not be included in Highlights. For

example, some labeling has included a contraindication in patients with hypersensitivity

to any of the drug products components, despite there being no such reports and no basisupon which to believe such a risk exists. For labeling being converted to PLR format,

these theoreticalcontraindications should be removed. If such data do exist, Highlights

should include the hypersensitivity contraindication, and the CONTRAINDICATIONS

section in the FPI should, in addition, describe the type and nature of the reactions thathave been reported. Similarly, circumstances under which the drug may be used with

caution are not contraindications and are not appropriate for inclusion.

8A draft guidance is available on this issue. See Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation

for FDAs current thinking on this topic. Once finalized, this guidance will represent the Agencys perspective onthis issue

12

7/21/2019 10009fnl 2-20-13

17/34


10. Warnings and Precautions ( 201.57(a)(10))

Information under the Warnings and Precautions heading must include a concise

summary of the most clinically significant safety concerns from the FPI that affect

decisions about whether to prescribe the drug, recommendations for patient monitoring to

ensure safe use of the drug, and measures that can be taken to prevent or mitigate harm (201.57(a)(10)). Individual risk topics should be presented in a bulleted format, with each

imparting a complete piece of information (e.g., identify the risk, its consequences, andrecommendations for the clinician to prevent or mitigate it, as appropriate). For example:

Infusion reactions: Severe reactions have been reported. Discontinue DRUG-X for

severe reactions; consider pre-treatment for cycles subsequent to milder reactions.(5.X).

The presentation should not merely be a list of subsection headings from Contents.Ambiguous and uninformative information (e.g., use with caution) and terminology that

describes a contraindication (e.g., do not use) should be avoided.

The most clinically significant safety concerns should be presented in Highlights;

however, not all of the safety information from the FPI will always be included in

Highlights. The order of the information should be the same as that of the FPI

WARNINGS AND PRECAUTIONS section, reflecting the nature and severity of therisks. As previously stated, it is generally not necessary or useful to repeat information if

it appears in other sections of Highlights.

11. Adverse Reactions ( 201.57(a)(11))

a. Most frequently occurring adverse reactions

Information under the Adverse Reactions heading must include (1) a listing of the most

frequently occurring adverse reactions, even if one or more are included elsewhere in

Highlights (e.g., under the Warnings and Precautions heading) and (2) the criteria used todetermine inclusion (e.g., frequency cutoff rate) ( 201.57(a)(11)(i)). The listing should

be concise, not lengthy or comprehensive, and reactions should be presented in

decreasing order of frequency. Specific terms should be used (e.g., neutropenia ratherthan hematologic) because general terms may not adequately describe the risk.

The list of adverse reactions identified as most frequently occurring or most commonis

usually generated from a table of adverse reactions from clinical trials in the FPI. Ratesof most common adverse reactions vary, but should be appropriate to the nature of a

drugs adverse reactions profile and the size and composition of the safety database. Ifadverse reaction profiles vary significantly for different indications, the most common

adverse reactions should be presented separately for each indication.

13

7/21/2019 10009fnl 2-20-13

18/34


b. Adverse reaction reporting contact information

Highlights must also contain adverse reaction reporting contact information, in bold type,

that includes the following ( 201.57(a)(11)(ii), (iii), (iv) and 201.57(d)(5)):

-

The verbatim statement To report SUSPECTED ADVERSE REACTIONS,contact followed by the manufacturers name and phone number for adverse

reaction reporting- The address of a manufacturers web site for voluntary reporting of adverse

reactions (only if such a web site exists)9

- FDAs phone number and web address for voluntary reporting of adverse reactions(see below).

FDAs phone numbers and web addresses for voluntary reporting of adverse

reactions:

For drug and biological products (other than vaccines)MedWatchPhone number: 1-800-FDA-1088

Web address: www.fda.gov/medwatch

For vaccines

VAERS

Phone number: 1-800-822-7967Web address: www.vaers.hhs.gov

10

For example, the completed adverse reaction reporting contact information statement for

a drug product would read:

To report SUSPECTED ADVERSE REACTIONS, contact [name of

manufacturer] at [manufacturers phone number] or FDA at 1-800-FDA-1088

or www.fda.gov/medwatch.

The intent of this requirement is to encourage reporting of suspected adverse reactions.The rule specifically requires the inclusion of a phone number and, if available, the web

address of the direct link to a site dedicated to adverse reaction reporting. Such dedicated

web sites and phone lines provide a structured process for reporting adverse reactions

(i.e., telephone interview, a form, or instructions for reporting), whereas an e-mailaddress or link to a company or product web site does not. An e-mail address or a link to

the homepage of a companys web site cannot be used to meet the requirement for

adverse reactions reporting contact information in Highlights ( 201.57(a)(11)(iv)).Although not specifically required in these labeling regulations, the phone number

9If a manufacturer does not have a web site for voluntary reporting of adverse reactions, the manufacturer is not

required to create one.10For vaccines, this web address is also used for reporting required by health care professionals.

14
http://www.fda.gov/medwatchhttp:///reader/full/www.vaers.hhs.govhttp://www.fda.gov/medwatchhttp://www.fda.gov/medwatchhttp:///reader/full/www.vaers.hhs.govhttp://www.fda.gov/medwatch

7/21/2019 10009fnl 2-20-13

19/34


provided should be a toll-free number to encourage reporting by practitioners andconsumers.

If more than one entity is responsible for the product (e.g., the product is manufactured

by one company and marketed by another, or the product is co-marketed), only one

contact should be listed (e.g., the name of the entity identified by agreement between thecompanies as the recipient of safety information).

12. Drug Interactions ( 201.57(a)(12))

Information under the Drug Interactions heading must include a concise summary ofthose drugs (or classes of drugs) or foods that interact or are predicted to interact in

clinically significant ways with the subject drug, and practical instructions for preventing

or managing the interaction ( 201.57(a)(12)).

Interaction information in Highlights should reflect the ordering of the DRUG

INTERACTIONS section in the FPI, which is based on the relative clinical significanceof the information. Descriptive subheadings of summary concepts (e.g., CYP3Ainhibitors) can precede specific information. Rarely, it may be appropriate to include

pertinent negative findings of drug interaction studies under this heading if the interaction

would otherwise be anticipated or is of special concern.

If there are no clinically significant drug interactions, the heading should be omitted from

Highlights. Information about lack of drug interactions or drug interactions that are notclinically relevant should not be included in Highlights.

Interactions with serious clinical consequences that are summarized elsewhere in

Highlights (e.g., in the Boxed Warning or under the Contraindications or Warnings andPrecautions heading) should be described in greater detail in the DRUG

INTERACTIONS section in the FPI and need not be repeated under the Drug

Interactions heading in Highlights.

Because some drugs have numerous clinically significant drug interactions, it may not be

possible to concisely summarize all the critical information in Highlights. In theseinstances, a statement can be included under the Drug Interactions heading in Highlights

that alerts the prescriber to the presence and significance of the drug interaction

information in the FPI.

13. Use in Specific Populations ( 201.57(a)(13))

Information under the Use in Specific Populations heading must include a concisesummary of any clinically important differences in response or recommendations for use

of the drug in specific populations from the FPI (e.g., differences between adult andpediatric responses, need for specific monitoring in patients with hepatic impairment) (

201.57(a)(13)). If multiple populations are described under this heading, they should be

presented in the same order in which they appear in the FPI.

15

7/21/2019 10009fnl 2-20-13

20/34


If there are no clinically important differences in response or recommendations for use of

the drug in specific populations, the heading should be omitted from Highlights.

Ordinarily, the absence of information about the safety and effectiveness of a drug in a

specific population (e.g., pregnant women, children) should not be included under this

heading. In unusual circumstances, if describing the absence of data provides importantinformation for the prescriber, the heading should be retained. For example, if a drug has

not been adequately studied in a specific patient population (e.g., those with hepaticimpairment), Highlights may include a bullet describing the lack of information if

deemed essential for prescribing decisions in that specific population.

The pregnancy category designation is not appropriate for inclusion in Highlights

because, in isolation, it tends to oversimplify the risks of drugs in pregnancy and, as a

result, may be confusing. Decisions about use of a drug in pregnancy should be based oncareful consideration of available data, not simply on a reference to the pregnancy

category. Information about the availability of a pregnancy registry and enrollment

information should not appear in Highlights because it is not essential information anddoes not affect prescribing decisions. Registry information should be included in thePregnancy subsection of the USE IN SPECIFIC POPULATIONS section of the FPI.

If information about use in specific populations is included under other headings inHighlights (e.g., Contraindications, Warnings and Precautions, Dosage and

Administration), it should not be repeated under this heading.

14. Patient Counseling Information Statement ( 201.57(a)(14))

Highlights must contain the statement See 17 for PATIENT COUNSELING

INFORMATIONin bold or, if the product has FDA-approved patient labeling, See 17for PATIENT COUNSELING INFORMATION and FDA-approved patientlabeling, or if the product has a Medication Guide, See 17 for PATIENT

COUNSELING INFORMATION and Medication Guide( 201.57(a)(14) and201.57(d)(5)). If the product has both a Medication Guide and another type of FDA-

approved patient labeling (e.g., Instructions for Use), the statement should refer only to

the Medication Guide. If the product has more than one type of FDA-approved patientlabeling other than a Medication Guide (e.g., Patient Package Insert, Patient Information,

Instructions for Use), the statement should refer only to FDA-approved patient labeling.

15. Revision Date ( 201.57(a)(15))

At the end of Highlights, the date of the most recent revision of the labeling must be

presented ( 201.57(a)(15)). The preferred format is Revised: Month Yearor Revised:Month/Yearin bold type (i.e., Revised: Apr 2011or Revised: 4/2011). In PLR

format, this statement replaces the revision date that appears at the end of labeling in theold format ( 201.56(e)(5)). A new approval or changes to the approved labeling will

trigger a new revision date. FDA-approved patient labeling or Medication Guides can

16

7/21/2019 10009fnl 2-20-13

21/34


have revision dates that differ from the revision date at the end of Highlights, ifappropriate.

For labeling requiring prior approval (e.g., original applications, efficacy

supplements, prior approval labeling supplements), the revision date would be the

date of application approval. Manufacturers should leave this field blank and FDAwill populate it at the time of approval.

For CBE supplement labeling ( 314.70(c)(6) and 601.12(f)(2)), the revision date

generally is the date of application receipt. Manufacturers should populate the

revision date field with the date they anticipate FDA will receive the supplement. Ifthe labeling text is changed by FDA, the revision date will be changed to the date of

CBE approval.

For annual report labeling, the revision date should reflect the date that the revisedlabeling is submitted to FDA. If all such changes are bundled and submitted once a

year with the annual report, the revision date should be the date of the receipt of theannual report.

VI. FORMATTING

The final rule includes formatting requirements (e.g., ordering, numbering, type size) that were

designed to enhance readability and accessibility of labeling information ( 201.57(d)).

Attention to the formatting requirements of Highlights is particularly important because the mostimportant prescribing information is presented in limited space (see Appendix E, which

illustrates a sample Highlights and Contents). Although Appendix E illustrates every possible

section and subsection, it is only an example, and not all drugs will have entries for all sections

or subsections presented. FDA recommends the use of a two-column format for Highlights andContents and use of adequate white space in Highlights (e.g., between each section) because

these formatting techniques enhance effective communication of the labeling information.

Beyond these requirements and recommendations, FDA expects that some flexibility informatting will be necessary because of variability in the type and quantity of labeling

information for different drugs. Other recommendations for formatting issues are described

below.

A. Subsection Headings

Some subsections are required (e.g., 8.1 Pregnancy, 12.1 Mechanism of Action) ( 201.56(d)(1)).

The use of additional subsection headings is encouraged to help organize and identify the contentof the information in the FPI (e.g., to identify individual warnings). Subsection headings that are

not useful for signaling the content of the subsection, such as General orMiscellaneousshouldbe avoided. Each subsection heading must be assigned a decimal number that corresponds to its

placement in the FPI ( 201.56(d)(2) and 201.57(c)).

Subheadings under a subsection may be used to help organize information within a subsection,

but they should not be assigned a numerical identifier with an additional decimal point (e.g.,

17

7/21/2019 10009fnl 2-20-13

22/34


12.3.1) nor should they appear in Contents. Instead, other formatting techniques (e.g., italics orunderlining) can be used to achieve emphasis.

B. Omitted Sections ( 201.56(d)(4))

Any section, subsection, or specific information that is clearly inapplicable must be omitted fromlabeling ( 201.56(d)(4)). Additionally, in most cases, when clinically relevant information

about a drug is not available, the section or subsection should be omitted. Examples ofappropriate omissions include the following:

The DRUG ABUSE AND DEPENDENCE section should be omitted for a drug that is

not a controlled substance and has no potential for abuse or dependence.

The subsection Geriatric Use in the USE IN SPECIFIC POPULATIONS section should

be omitted for a drug indicated only in neonates.

When a section or subsection is omitted from the FPI, it must also be omitted from the Contents

( 201.56(d)(4)). The heading Full Prescribing Information: Contents must be followed by anasterisk and the following statement must appear at the end of the Contents: *Sections or

subsections omitted from the full prescribing information are not listed ( 201.56(d)(4)). When

there is an omission from the labeling, the numbering outlined in 201.56(d)(1) should bepreserved (i.e., subsequent sections and subsections are not renumbered).

In most cases when clinically relevant information about a drug is not available, the section or

subsection should be omitted. In a few cases, describing the absence of data can provideimportant information for the prescriber, and, in these instances, the section or subsection should

be included. For example, if a drug has not been adequately studied in a patient population withrenal impairment, the labeling should typically include a Renal Impairment subsection under

USE IN SPECIFIC POPULATIONS stating the lack of information.

C. Cross-References

Cross-referencing is encouraged, and in some cases required (e.g., 201.57(c)(1), (c)(6)(iv) and(c)(15)(ii)) because it refers the reader to more or related information on the topic and reduces

the need to repeat detailed information about a similar issue in several different sections (see

IV.B of this guidance for more information).

The preferred presentation of cross-references in Highlights is the numerical identifier in

parentheses following the summarized labeling information (e.g., (5.1)). The preferred

presentation of cross-references in the FPI is the section heading followed by the numericalidentifier (e.g., [see Warnings and Precautions (5.1)]). Because cross-references are embedded

in the text in the FPI, we encourage the use of italics to achieve emphasis.

D. Type Size and Font Type

The final rule requires different minimum type sizes for trade labeling (i.e., labeling on or withinthe package from which the drug is to be dispensed, including product samples) and for labeling

18

7/21/2019 10009fnl 2-20-13

23/34


disseminated in other settings (e.g., labeling that accompanies prescription drug promotionalmaterials) (see 201.57(d)(6)). Appendix D shows minimum type size requirements for labeling

in the PLR format ( 201.57) and in the old format ( 201.80), including requirements for FDA-

approved patient labeling ( 201.57(c)(18) and 201.80(f)(2))). FDA encourages a minimum

type size of 10 points for all FDA-approved patient labeling.

There is no requirement for a specific font type (or typeface) for labeling, but the font type

should be clear and legible. For example, narrow font types (e.g., Arial Narrow) are notrecommended because they are difficult to read and may render the labeling illegible.

E. Use of Abbreviations

Once an abbreviation for a term is defined in Highlights, FDA recommends redefining it the first

time it is used in the FPI. Because labeling is frequently used to find a specific piece ofinformation and the labeling may not be read from beginning to end, an acronym may be several

pages away from where it was first defined in Highlights.

Unambiguous, commonly understood abbreviations (e.g., mg for milligrams) do not need to bedefined. Abbreviations for units of measure (e.g., mg, mL) should be consistent within container

and carton labeling. FDA recommends that Latin abbreviations (e.g., QD, QID) be avoided

because of the greater potential for medication errors should an abbreviation be misread.11

VII. PROCEDURAL INFORMATION

A. Applications Covered by the Final Rule

Section 201.56(b)(1) provides that the final rule applies to prescription drug products with a newdrug application (NDA), biologics license application (BLA), or efficacy supplement that

is submitted on or after June 30, 2006 (the effective date of the final rule),

is pending with the Agency on June 30, 2006, or

was approved in the 5 years prior to June 30, 2006.

Although FDA recognizes the effort involved in revising labeling, the Agency strongly believes

that the PLR format is an important advance in communicating drug information. Therefore, we

encourage applicants with products to which the final rule does not apply to voluntarily convert

the labeling of their products to the PLR format.

1. New NDAs, BLAs, and Efficacy Supplements

Draft labeling for new NDAs, BLAs, and efficacy supplements must be submitted in the

PLR format ( 201.56(c)(1)).

11For additional information on abbreviations and dose designations that can lead to medication errors, see the

ISMP List of Error-Prone Abbreviations, Symbols, and Dose Designations

http://www.ismp.org/tools/errorproneabbreviations.pdf.

19
http:///reader/full/misread.11http:///reader/full/misread.11http://www.ismp.org/tools/errorproneabbreviations.pdfhttp:///reader/full/misread.11http://www.ismp.org/tools/errorproneabbreviations.pdf

7/21/2019 10009fnl 2-20-13

24/34


The following efficacy supplements trigger the requirement to revise labeling to the PLR

format:

Adding or modifying an indication or claim

Revising the dose or dose regimen Providing for a new route of administration

Making a comparative efficacy claim naming another product

Significantly altering the intended patient population

Providing for, or providing evidence of effectiveness necessary for, the traditional

approval of a product originally approved under subpart H of part 314 or part 601

Incorporating other information based on at least one adequate and well-controlled

clinical study

Pediatric supplements in response to written requests and the Pediatric ResearchEquity Act (PREA) of 2007

12

Examples of supplements that do not trigger the requirements to revise labeling to thePLR format include NDA supplements for a new tablet strength; supplements that

provide bioequivalence information, chemistry, manufacturing, and controls, also known

as a CMC supplement, including one that contains clinical data but for which the data

do not affect labeling (e.g., reformulation); and supplements that add new riskinformation (e.g., a new contraindication, warning).

2. Approved Applications

The timing for submitting labeling in the PLR format is based on the implementation plan

(see 201.56(c) and Appendix A), but an applicant can voluntarily convert product

labeling to the PLR format before the date specified in the implementation plan and isencouraged to do so. When more than one approval for the same product occurred in the

5 years prior to the effective date of the final rule (e.g., NDA and efficacy supplement),the date of the most recent approval determines the timing of submission of labeling in

the PLR format according to the implementation plan.

The labeling must be submitted as aprior approvallabeling supplement.13

After labeling

is approved in the PLR format, any subsequent changes to Highlights, other than

identified minor exceptions, require submission of a prior approval supplement (314.70(b), (c), and (d) and 601.12(f)).

3. Submitting Draft Labeling to FDA for Review

To facilitate FDAs review of labeling, when a significant amount of new information is

being added to the labeling at the same time that the labeling is being converted to the

12Section 505A and 505B of the Federal Food, Drug & Cosmetic Act, as amended by the Food and Drug

Administration Amendments Act of 2007 (P. L. 110-85)13See 314.70(b) and 601.12(f) about supplements requiring FDA approval before the change is made.

20
http:///reader/full/supplement.13http:///reader/full/supplement.13http:///reader/full/supplement.13

7/21/2019 10009fnl 2-20-13

25/34


PLR format (e.g., an efficacy supplement that also converts labeling to the PLR format),we recommend that the following versions of labeling be submitted as appropriate:

Labeling in the old format

Annotated labeling in the old format explaining how existing text was incorporated

into the PLR format Acleanversion (no redline/strikeout) in the PLR format withoutthe new

information

The aboveclean version in the PLR format withthe new information (in

redline/strikeout)

For the example listed above, if the efficacy supplement is to be reviewed in a divisionother than the one that managed the original application, two supplements should be

submitted (i.e., a labeling supplement and an efficacy supplement).

Applicants should explain significant or notable changes in wording or content, or

relocation of information to a different section, and how the decisions to make thosechanges were made. For submissions covering only a conversion of existing labeling toPLR format (without adding new information), the applicant should mark clearly on the

cover letter, Labeling/PLR Conversionto facilitate identification of the type of

submission for FDA.

B. Changes to the Regulations for Applications Not Covered by the Final Rule

FDA has also made minor amendments to the labeling regulations for prescription drug andbiological products not subject to the PLR content and format requirements (see 201.56(e)

and 201.80). Section 201.80 remains largely unchanged from previous labeling regulations,

except for minor revisions to the REFERENCES section and the requirement to append FDA-approved patient labeling to the prescribing information by June 30, 2007. As always, labeling

must be informative and accurate and neither promotional in tone nor false or misleading in any

particular ( 201.56(a)(3)). Therefore, the applicant should review the labeling at least annually

for outdated information. Removing outdated references could be submitted in the AnnualReport.

C. Appending FDA-Approved Patient Labeling

The final rule required that by June 30, 2007, any FDA-approved patient labeling either

accompany the labeling or be reprinted immediately following the last section of the labeling (

201.56(e)(6), 201.57(c)(18) and 201.80(f)(2)).14

This requirement applies to the labeling of alldrugs, not just those subject to the PLR format requirements. The final rule provides the option

of either reprinting the FDA-approved patient labeling (including Medication Guides)immediately following the last section of labeling or having the FDA-approved patient labeling

accompany the labeling as a separate document (e.g., included in the carton with the drug).

14The term FDA-approved patient labelingrefers to any labeling that has been reviewed and approved by FDA that

provides information for patients and is intended for distribution to patients who are prescribed a drug.

21
http:///reader/full/201.80(f)(2)).14http:///reader/full/201.80(f)(2)).14http:///reader/full/201.80(f)(2)).14

7/21/2019 10009fnl 2-20-13

26/34


In addition, any FDA-approved patient labeling must be referenced in the PATIENT

COUNSELING INFORMATION section ( 201.57(c)(18) in the PLR format or in the

Information for Patients subsection ( 201.80(f)(2) in the old format). A statement referring the

reader to FDA-approved patient labeling should appear at the beginning of the section or

subsection.

The FDA-approved patient labeling should not be a numbered subsection under the PATIENTCOUNSELING INFORMATION section in the FPI or listed in Contents, but appended or

reprinted after the last section of labeling.

Including only the FDA-approved patient labeling as the content of the PATIENT

COUNSELING INFORMATION section does not meet the requirements of the final rule (

201.57(c)(18) and 201.80(f)(2)). FDA-approved patient labeling and the information in thePATIENT COUNSELING INFORMATION section have distinct purposes. The PATIENT

COUNSELING INFORMATION section of the FPI is written for health care professionals and

contains the information that is important to convey to patients when the drug is beingprescribed, dispensed, or administered. The FDA-approved patient labeling is written forpatients to provide them with information about the drug that has been prescribed. FDA believes

that both of these are important tools for providing information to patients.

D. Submitting Electronic Versions of Labeling

For information about submitting labeling electronically, applicants should consult theinformation and guidances for industry on FDAs web site on Structured Product Labeling

Resources.15

E. Waivers and CBE Supplements

Waivers: Requests to waive a labeling requirement under 314.90(a) or 201.58 should be

submitted directly to the application with any related communication directed to the

responsible review division. A waiver request may pertain to a labeling requirementdescribed in 201.56, 201.57, 201.80, or 314.50(l)(i). The applicant should clearly identify

the submission as a request for a waiver.

Waivers of the one-half page Highlights requirement: The PLR regulations require thatHighlights, excluding the boxed warning, be limited in length to one-half page (

201.57(d)(8)). Applicants should strive for this one-half page limit, using recommendations

included in this guidance (e.g., avoiding redundancy of information, use of directivelanguage, and inclusion of succinct bulleted lists). However, FDA recognizes that under

certain circumstances, particularly when a product has many indications or many serious

warnings and precautions that merit inclusion in Highlights, it may not be possible toaccommodate all the required information within one-half page. In this case, the applicant

15 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.

22
http:///reader/full/Resources.15http:///reader/full/Resources.15http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htmhttp:///reader/full/Resources.15http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm

7/21/2019 10009fnl 2-20-13

27/34


can submit a waiver request with the submission (e.g., NDA, BLA, efficacy supplement, orlabeling supplement) (see 201.58.).

The applicant should prominently identify the submission as one that includes a waiver

request. In the waiver request, the applicant should explain why the one-half page

requirement cannot be met. FDA will discuss the waiver request with the applicant duringthe review process and will formally document its decision in an action letter to the applicant.

Changes to Highlights through a CBE supplement: With minor exceptions, changes toHighlights require a prior approval supplement ( 314.70 and 601.12). If the labeling is

already approved in the PLR format and the proposed change(s) qualify for a CBE

supplement under 314.70(c) and 601.12(f), a prior approval supplement is not needed aslong as the change does not warrant inclusion in Highlights (e.g., addition of an adverse

reaction to the ADVERSE REACTIONS section in the FPI). If, in the opinion of the

applicant, the new information warrants inclusion in Highlights or will be listed under RecentMajor Changes in Highlights (i.e., a change to the BOXED WARNING,

CONTRAINDICATIONS, OR WARNINGS AND PRECAUTIONS sections), the applicantshould notify the appropriate review division about the proposed change to the labeling. Thereview division may permit changes to Highlights through a CBE supplement after

consideration of the new information.

F. Class Labeling

1. Mandated Statements

In some instances, a statement for a drug or class of drugs is required by regulation to be

included in a particular section of the labeling (e.g., 21 CFR 310.517 requires that

labeling for oral hypoglycemics of the sulfonylurea class include a statement in theWARNINGS section). When converting labeling to the PLR format, any required

statement should be included in the corresponding section in the PLR format (e.g., a

statement required to be included in the BOXED WARNING in the old format should be

included in the BOXED WARNING in the PLR format). For sections that have beenaltered or eliminated, see Appendix C for the location of the statement in the PLR format.

In cases where the regulation requires a statement, but the rule does not specify where thestatement should appear, FDA will consider, on a case-by-case basis where those

statements should appear in the PLR format. Whether a specific statement required by

regulation must appear in Highlights will be determined by FDA.

2. Class Labeling Statements That Are Not Mandated by Regulation

In some cases, the labeling of all members of a class of drugs includes identical

statements, even though they are not mandated by regulation. These class labeling

statements describe a risk or effect that is typically associated with members of the class,

based on what is known about the pharmacology or chemistry of the drugs. For example,

23

7/21/2019 10009fnl 2-20-13

28/34


the boxed warning about the risk of using an ACE inhibitor during the second and thirdtrimesters of pregnancy is uniformly presented in all labeling for this class of drugs.

To ensure consistent presentation of class labeling statements within drug classes, FDA

will determine the appropriate content and location of a class labeling statement in

Highlights and the FPI.

G. Abbreviated New Drug Application (ANDA) Products

Under 21 CFR 314.94(a)(8), the labeling of a drug product submitted for approval under an

ANDA must be the same as the labeling of the listed drug referenced in the ANDA, except forchanges required because of the following:

Differences have been approved under a suitability petition filed under 21 CFR 314.93.

The ANDA product and the reference listed drug are produced or distributed by different

manufacturers.

Aspects of the listed drugs labeling are protected by patent or exclusivity.

Thus, if the labeling of the reference listed drug is converted to the PLR format, the labeling of

the ANDA product must also be revised in accordance with 21 CFR 314.127(a)(7).

H. 505(b)(2) NDA Products

In general, the applicant submitting an application under section 505(b)(2) of the FD&C Actneed not wait for changes to be made to the referenced products labeling to convert its labeling

to the PLR format. For specific cases when an applicant may feel such a delay is warranted, a

waiver from the requirements for the PLR format can be requested. If the section 505(b)(2)

product labeling is converted to the PLR format before the referenced product, and substantialchanges are made to sections referenced by the section 505(b)(2) product when the referenced

product labeling is converted, FDA may request additional changes to the labeling of the section

505(b)(2) product in accordance with existing regulations and policies.

I. Manufacturer Information

Under 201.1, labeling must include the name and place of business of the manufacturer,

packer, or distributor. Traditionally, this has been printed at the end of the labeling (after the

HOW SUPPLIED section). In the PLR format, manufacturer information should be located at

the end of the labeling, after the PATIENT COUNSELING INFORMATION section. If the

product has FDA-approved patient labeling that is not a separate document or not intended to bedetached and distributed to patients, the manufacturer information should be located at the end of

the labeling, after the FDA-approved patient labeling. If the FDA-approved patient labeling is aseparate document or is to be detached and distributed to patients, the manufacturer information

should be located both after the PATIENT COUSELING INFORMATION section and after the

FDA-approved patient labeling.

24

7/21/2019 10009fnl 2-20-13

29/34


VIII. ADDITIONAL LABELING GUIDANCES

FDA has issued several additional guidances for industry on prescription drug labeling. FDA

guidances are available on FDAs guidance web site.

(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/default.htm.) The website is updated regularly as new or revised guidances are published.

25
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/default.htmhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/default.htm

7/21/2019 10009fnl 2-20-13

30/34


APPENDIX A Implementation Plan

Applications (NDAs, BLAs, and Efficacy

Supplements) Required to Conform to

PLR Labeling Requirements

Time by Which Conforming Labeling

Must Be Submitted to the Agency for

ApprovalApplications submitted on or after June 30,

2006

Applications pending on June 30, 2006,

and applications approved any time fromJune 30, 2005, up to and including June 30,

2006

Applications approved any time from June30, 2004, up to and including June 29,

2005

Applications approved any time from June

30, 2003, up to and including June 29,

2004


30, 2002, up to and including June 29,

2003


30, 2001, up to and including June 29,2002

Applications approved prior to June 30,2001

Time of submission

June 30, 2009

June 30, 2010

June 30, 2011

June 30, 2012

June 30, 2013

Voluntarily at any time

26

7/21/2019 10009fnl 2-20-13

31/34


APPENDIX B Prescription Drug Labeling Sections

Old Format* PLR Format**

Description HIGHLIGHTS OF PRESCRIBING INFORMATIONClinical Pharmacology Product Names, Other Required Information

Indications and Usage Boxed WarningContraindications Recent Major Changes

Warnings Indications and UsagePrecautions Dosage and Administration

Adverse Reactions Dosage Forms and Strengths

Drug Abuse and Dependence ContraindicationsOverdosage Warnings and Precautions

Dosage and Administration Adverse Reactions

How Supplied Drug Interactions

Use in Specific PopulationsOptional sections:

Animal Pharmacology FULL PRESCRIBING INFORMATION: CONTENTSand/or Animal ToxicologyClinical Studies FULL PRESCRIBING INFORMATIONReferences Boxed Warning

1 Indications and Usage2 Dosage and Administration

3 Dosage Forms and Strengths

4 Contraindications

5 Warnings and Precautions6 Adverse Reactions

7 Drug Interactions

8 Use in Specific Populations9 Drug Abuse and Dependence

10 Overdosage

11 Description12 Clinical Pharmacology

13 Nonclinical Toxicology

14 Clinical Studies15 References

16 How Supplied/Storage and Handling

17 Patient Counseling Information

* As required by 21 CFR 201.56(e) and 201.80.

**As required by 21 CFR 201.56(d) and 201.57

27

7/21/2019 10009fnl 2-20-13

32/34


APPENDIX C Reorganizing Labeling Sections

Location in Old Format Location in FPI in PLR Format

Boxed Warning

Boxed WarningDescription Description

Clinical Pharmacology Clinical PharmacologyIndications and Usage Indications and Usage

Contraindications Contraindications

Warnings Warnings and PrecautionsPrecautions

General Warnings and Precautions

Information for Patients Patient Counseling InformationLaboratory Tests Warnings and Precautions

Drug Interactions Drug Interactions

Drug/Laboratory TestInteractions Warnings and PrecautionsCarcinogenesis, Mutagenesis,

Impairment of Fertility Nonclinical Toxicology (Carcinogenesis,

Mutagenesis, Impairment of Fertility)Pregnancy Use in Specific Populations (Pregnancy)

Labor and Delivery Use in Specific Populations (Labor and Delivery)

Nursing Mothers Use in Specific Populations (Nursing Mothers)Pediatric Use Use in Specific Populations (Pediatric Use)

Geriatric Use Use in Specific Populations (Geriatric Use)

Adverse Reactions Adverse Reactions

Drug Abuse and Dependence

Drug Abuse and DependenceOverdosage Overdosage

Dosage and Administration Dosage and Administration

How Supplied Dosage Forms and Strengths

How Supplied/Storage and Handling

Animal Pharmacology

and/or Animal Toxicology Nonclinical Toxicology (Animal Toxicology and/orPharmacology)

Clinical Studies Clinical Studies

References References

28

7/21/2019 10009fnl 2-20-13

33/34


APPENDIX D Type Size Requirements for Labeling and FDA-Approved Patient

Labeling Included with Labeling

Type Size

Requirementsfor Labeling

FDA-Approved Patient Labeling

Includedwith Labeling

Type Size

Requirementsfor FDA-Approved

Patient Labeling

PLR Format (21 CFR 201.57)

Trade Labeling

(i.e., labelingon or within

the package

from which the

drug is to bedispensed)

Minimum 6-point

type

FDA-approved patient labeling that

is not for distribution to patients

Minimum 6-point type

Any FDA-approved patient labeling(except a Medication Guide) that is

for distribution to patients

Minimum 6-point type*

Medication Guide that is fordistribution to patients

Minimum 10-pointtype

Other Labeling

(e.g., labelingaccompanying

promotionalmaterials)

10009fnl 2-20-13

Documents

Transcript of 10009fnl 2-20-13